Targeted Therapy with Radium-223 of Bone Metastases

  • Sergio Baldari
  • Alessandro Sindoni
  • Laura Evangelista
  • Emilio Bombardieri


223Ra is a targeted alpha therapy approved for treatment of metastatic prostate cancer with symptomatic bone metastases and without known visceral metastases. It documented an overall survival benefit, increased time to symptomatic skeletal event, improved quality of life and good safety profile in the pivotal trial ALSYMPCA.

The patient suitable for treatment must present at least two sites of osseous localization at bone scan, with no visceral involvement and lymph nodal disease within 3 cm diameter (short axis).

First data from clinical practice and from expanded access program confirmed safety and efficacy and highlighted that early use is related to completion of six cycles and better clinical outcome.

During treatment, it is important to evaluate pain response, clinical outcome, complete blood count and ALP at each cycle, while PSA must be assessed only every three cycles. Imaging modalities should be repeated at baseline (to select the right patient) and after at least 8 weeks from last administration (to assess the disease response); only in case of clinical suspicion of relapse, the same modalities could be repeated during treatment to exclude a disease progression.


Bone metastases Metastatic castration-resistant prostate cancer Radium-223 Follow-up Safety 


  1. 1.
    Picciotto M, Franchina T, Russo A, Ricciardi GRR, Provazza G, Sava S, Baldari S, Caffo O, Adamo V. Emerging role of Radium-223 in the growing therapeutic armamentarium of metastatic castration-resistant prostate cancer. Expert Opin Pharmacother. 2017;18:899–908.CrossRefPubMedGoogle Scholar
  2. 2.
    Kassis AI. Therapeutic radionuclides: biophysical and radiobiologic principles. Semin Nucl Med. 2008;38:358–66.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Harrison MR, Wong TZ, Armstrong AJ, George DJ. Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease. Cancer Manag Res. 2013;5:1–14.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Logothetis CJ, Gallick GE, Maity SN, et al. Molecular classification of prostate cancer progression: foundation for marker-driven treatment of prostate cancer. Cancer Discov. 2013;3:849–61.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Henriksen G, Breistøl K, Bruland ØS, Fodstad Ø, Larsen RH. Significant antitumor effect from bone-seeking, alpha-particle emitting (223)Ra demonstrated in an experimental skeletal metastases model. Cancer Res. 2002;62:3120–5.PubMedGoogle Scholar
  6. 6.
    Suominen MI, Rissanen JP, Käkönen R, Fagerlund KM, Alhoniemi E, Mumberg D, Ziegelbauer K, Halleen JM, Käkönen SM, Scholz A. Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis. J Natl Cancer Inst. 2013;105:908–16.CrossRefPubMedGoogle Scholar
  7. 7.
    Abou DS, Ulmert D, Doucet M, Hobbs RF, Riddle RC, Thorek DL. Whole-body and microenvironmental localization of Radium-223 in naïve and mouse models of prostate cancer metastasis. J Natl Cancer Inst 2016; 108: pii: djv380.Google Scholar
  8. 8.
    Suominen MI, Fagerlund KM, Rissanen JP, Konkol YM, Morko JP, Peng ZQ, Alhoniemi EJ, Laine SK, Corey E, Mumberg D, Ziegelbauer K, Käkönen SM, Halleen JM, Vessella RL, Scholz A. Radium-223 inhibits osseous prostate cancer growth by dual targeting of cancer cells and bone microenvironment in mouse models. Clin Cancer Res. 2017;23(15):4335–46.CrossRefPubMedGoogle Scholar
  9. 9.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65:5–29.CrossRefPubMedGoogle Scholar
  10. 10.
    Alemayehu B, Buysman E, Parry D, Becker L, Nathan F. Economic burden and healthcare utilization associated with castration-resistant prostate cancer in a commercial and medicare advantage US patient population. J Med Econ. 2010;13:351–61.CrossRefPubMedGoogle Scholar
  11. 11.
    Ritch CR, Cookson MS. Advances in the management of castration resistant prostate cancer. BMJ. 2016;355:i4405.CrossRefPubMedGoogle Scholar
  12. 12.
    Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, Chin JL, Vinholes JJ, Goas JA, Chen B. Zoledronic acid prostate cancer study group: a randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458–68.CrossRefPubMedGoogle Scholar
  13. 13.
    Fizazi K, Beuzeboc P, Lumbroso J, Haddad V, Massard C, Gross-Goupil M, Di Palma M, Escudier B, Theodore C, Loriot Y, Tournay E, Bouzy J, Laplanche A. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castration-resistant prostate cancer. J Clin Oncol. 2009;27:2429–35.CrossRefPubMedGoogle Scholar
  14. 14.
    Minutoli F, Herberg A, Spadaro P, Restifo Pecorella G, Baldari S, Aricò D, Altavilla G, Baldari S. [186Re]HEDP in the palliation of painful bone metastases from cancers other than prostate and breast. Q J Nucl Med Mol Imaging. 2006;50:355–62.PubMedGoogle Scholar
  15. 15.
    Fuster D, Herranz D, Vidal-Sicart S, et al. Usefulness of strontium-89 for bone pain palliation in metastatic breast cancer patients. Nucl Med Commun. 2000;21:623–6.CrossRefPubMedGoogle Scholar
  16. 16.
    Kraeber-Bodéré F, Campion L, Rousseau C, et al. Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement. Eur J Nucl Med. 2000;27:1487–93.CrossRefPubMedGoogle Scholar
  17. 17.
    Ashayeri E, Omogbehin A, Sridhar R, et al. Strontium 89 in the treatment of pain due to diffuse osseous metastases: a university hospital experience. J Natl Med Assoc. 2002;94:706–11.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Gunawardana DH, Lichtenstein M, Better N, et al. Results of strontium-89 therapy in patients with prostate cancer resistant to chemotherapy. Clin Nucl Med. 2004;29:81–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Liepe K, Kotzerke J. A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases. Nucl Med Commun. 2007;28:623–30.CrossRefPubMedGoogle Scholar
  20. 20.
    Pacilio M, Ventroni G, De Vincentis G, Cassano B, Pellegrini R, Di Castro E, Frantellizzi V, Follacchio GA, Garkavaya T, Lorenzon L, Ialongo P, Pani R, Mango L. Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting (223)Ra-dichloride. Eur J Nucl Med Mol Imaging. 2016;43:21–33.CrossRefPubMedGoogle Scholar
  21. 21.
    Correa-González L, Arteaga de Murphy C, Pichardo-Romero P, Pedraza-López M, Moreno-García C, Correa-Hernández L. (153)Sm-EDTMP for pain relief of bone metastases from prostate and breast cancer and other malignancies. Arch Med Res. 2014;45:301–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, Salberg G, Bruland OS. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res. 2005;11:4451–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, Lennernäs B, Petersson U, Johannessen DC, Sokal M, Pigott K, Yachnin J, Garkavij M, Strang P, Harmenberg J, Bolstad B, Bruland OS. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007;8:587–94.CrossRefPubMedGoogle Scholar
  24. 24.
    Parker C, Nilsson S, Heinrich D, Helle SI, O'Sullivan JM, Fosså SD, Chodacki A, Wiechno P, Logue J, Seke M, Widmark A, Johannessen DC, Hoskin P, Bottomley D, James ND, Solberg A, Syndikus I, Kliment J, Wedel S, Boehmer S, Dall'Oglio M, Franzén L, Coleman R, Vogelzang NJ, O'Bryan-Tear CG, Staudacher K, Garcia-Vargas J, Shan M, Bruland ØS, Sartor O, ALSYMPCA Investigators. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.CrossRefPubMedGoogle Scholar
  25. 25.
    Sartor O, Hoskin P, Coleman RE, et al. Chemotherapy following radium-223 dichloride treatment in ALSYMPCA. Prostate. 2016;76:905–16.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Alva A, Nordquist L, Daignault S, George S, Ramos J, Albany C, Isharwal S, McDonald M, Campbell G, Danchaivijitr P, Yentz S, Anand A, Yu EY. Clinical correlates of benefit from Radium-223 therapy in metastatic castration resistant prostate cancer. Prostate. 2017;77:479–88.CrossRefPubMedGoogle Scholar
  27. 27.
  28. 28.
    Baldari S, Boni G, Bortolus R, CAffo O, Conti G, De Vincentis G, Monari F, Procopio G, Santini D, Seregni E, Valdagni R. Management of metastatic castration-resistant prostate cancer: a focus on radium-223. Crit Rev Oncol Hematol. 2017;113:43–51.CrossRefPubMedGoogle Scholar
  29. 29.
    Sartor AO, Heinrich D, Mariados N. Radium-223 (Ra-223) re-treatment (Re-tx): first experience from an international, multicenter, prospective study in patients (Pts) with castration-resistant prostate cancer and bone metastases (mCRPC). J Clin Oncol. 2016;34(Suppl 2S):197. Dent AbstrCrossRefGoogle Scholar
  30. 30.
    Zimmerman BE, Bergeron DE, Cessna JT, Fitzgerald R, Pibida L. Revision of the NIST standard for (223)Ra: new measurements and review of 2008 data. J Res Natl Inst Stand Technol. 2015;120:37–57.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Prior JO, Gillessen S, Wirth M, Dale W, Aapro M, Oyen WJG. Radiopharmaceuticals in the elderly cancer patient: practical considerations, with a focus on prostate cancer therapy: a position paper from the International Society of Geriatric Oncology Task Force. Eur J Cancer. 2017;77:127–39.CrossRefPubMedGoogle Scholar
  32. 32.
    Miyazaki KS, Kuang Y, Kwee SA. Changes in skeletal tumor activity on (18)F-choline PET/CT in patients receiving (223)radium radionuclide therapy for metastatic prostate cancer. Nucl Med Mol Imaging. 2015;49:160–4.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Ahmadzadehfar H, Schlenkhoff CD, Rogenhofer S, Yordanova A, Essler M. 68Ga-PSMA-11 PET represents the tumoricidal effect of 223Ra in a patient with castrate-resistant metastatic prostate cancer. Clin Nucl Med. 2016;41:695–6.CrossRefPubMedGoogle Scholar
  34. 34.
    Seibel MJ. Biochemical markers of bone turnover: part I: biochemistry and variability. Clin Biochem Rev. 2005;26:97–122.PubMedPubMedCentralGoogle Scholar
  35. 35.
    Jung K, Lein M, Stephan C, Von Hösslin K, Semjonow A, Sinha P, Loening SA, Schnorr D. Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications. Int J Cancer. 2004;111:783–91.CrossRefPubMedGoogle Scholar
  36. 36.
    Berruti A, Tucci M, Mosca A, Tarabuzzi R, Gorzegno G, Terrone C, Vana F, Lamanna G, Tampellini M, Porpiglia F, Angeli A, Scarpa RM, Dogliotti L. Predictive factors for skeletal complications in hormone-refractory prostate cancer patients with metastatic bone disease. Br J Cancer. 2005;93:633–8.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Smith MR, Cook RJ, Coleman R, Brown J, Lipton A, Major P, Hei YJ, Saad F. Predictors of skeletal complications in men with hormone-refractory metastatic prostate cancer. Urology. 2007;70:315–9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cook RJ, Coleman R, Brown J, Lipton A, Major P, Hei YJ, Saad F, Smith MR. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res. 2006;12(11 Pt 1):3361–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Som A, Tu SM, Liu J, Wang X, Qiao W, Logothetis C, Corn PG. Response in bone turnover markers during therapy predicts overall survival in patients with metastatic prostate cancer: analysis of three clinical trials. Br J Cancer. 2012;107:1547–53.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Fox JJ, Morris MJ, Larson SM, Schöder H, Scher HI. Developing imaging strategies for castration resistant prostate cancer. Acta Oncol. 2011;50(Suppl 1):39–48.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Dennis ER, Jia X, Mezheritskiy IS, Stephenson RD, Schoder H, Fox JJ, Heller G, Scher HI, Larson SM, Morris MJ. Bone scan index: a quantitative treatment response biomarker for castration-resistant metastatic prostate cancer. J Clin Oncol. 2012;30:519–24.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sartor O, Coleman RE, Nilsson S, et al. 3-year follow-up of chemotherapy following radium-223 dichloride (Ra-223) in castration-resistant prostate cancer (CRPC) patients (Pts) with symptomatic bone metastases (Mets) from ALSYMPCA. Presented at: European Cancer Congress 2015. Vienna, Austria: Poster session. Abstract 2510.Google Scholar
  43. 43.
    Evangelista L, Bertoldo F, Boccardo F, Conti G, Menchi I, Mungai F, Ricardi U, Bombardieri E. Diagnostic imaging to detect and evaluate response to therapy in bone metastases from prostate cancer: current modalities and new horizons. Eur J Nucl Med Mol Imaging. 2016;43:1546–62.CrossRefPubMedGoogle Scholar
  44. 44.
    Withofs N, Grayet B, Tancredi T, Rorive A, Mella C, Giacomelli F, Mievis F, Aerts J, Waltregny D, Jerusalem G, Hustinx R. 18F-fluoride PET/CT for assessing bone involvement in prostate and breast cancers. Nucl Med Commun. 2011;32:168–76.CrossRefPubMedGoogle Scholar
  45. 45.
    Pacilio M, Cassano B, Chiesa C, Giancola S, Ferrari M, Pettinato C, Amato E, Fioroni F, Lorenzon L, Pellegrini R, Di Castro E, Pani R, Cremonesi M. The Italian multicentre dosimetric study for lesion dosimetry in (223)Ra therapy of bone metastases: calibration protocol of gamma cameras and patient eligibility criteria. Phys Med. 2016;32:1731–7.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Sergio Baldari
    • 1
  • Alessandro Sindoni
    • 1
  • Laura Evangelista
    • 2
  • Emilio Bombardieri
    • 3
  1. 1.Department of Biomedical and Dental Sciences, and of Morphological and Functional ImagesUniversity of MessinaMessinaItaly
  2. 2.Veneto Institute of Oncology IOV – IRCCSPaduaItaly
  3. 3.Department of Nuclear MedicineHumanitas Gavazzeni HospitalBergamoItaly

Personalised recommendations